In vivo thromboxane‐dependent platelet activation is persistently enhanced in subjects with impaired glucose tolerance
Francesca SantilliFrancesco ZaccardiRossella LianiGiovanna PetrucciPaola SimeoneDario PitoccoRomina TripaldiAlessandro RizziGloria FormosoAlfredo PontecorviE AngelucciFrancesca PagliacciaMaria GolatoFrancesca De LevaEster VitacolonnaBianca RoccaAgostino ConsoliCarlo Patrono
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Abstract Background Impaired glucose tolerance (IGT) is associated with increased cardiovascular morbidity and mortality. Enhanced thromboxane (TX)‐dependent platelet activation plays a pivotal role in atherothrombosis and characterizes type 2 diabetes mellitus (DM). Whether this also pertains to IGT is currently unknown. We investigated whether TXA 2 ‐dependent platelet activation, as reflected by 11‐dehydro‐TXB 2 (TXM) urinary excretion, is comparably abnormal in IGT as in DM, is persistent over long‐term follow‐up, changes as a function of metabolic disease progression, and is influenced by food intake. Methods We prospectively investigated subjects with IGT (n = 48) and two control groups with DM diagnosed either less than 12 months (n = 60) or 12 months or more (n = 58). Results Baseline TXM excretion was comparable between subjects with IGT and DM, with no evidence of a circadian variation. During a 36‐month follow‐up, urinary TXM excretion was stable over time in the DM groups, while tended to increase in subjects with IGT. Increasing urinary TXM excretion over time was observed in the subjects who progressed to diabetes vs nonprogressors. Conclusions We conclude that TXA 2 ‐dependent platelet activation was at least as high in IGT as in patients with DM and further increased over time, especially in those who progressed to overt diabetes.Several agents inhibit thromboxane synthesis in platelets so might be expected to modulate the arachidonate- induced platelet release reaction and the platelet aggregation that accompanies it. Such agents include the nonsteroidal anti-inflammatory agents (NSAIAs) that inhibit cyclo-oxygenase activity, the selective inhibitor of thromboxane synthetase UK-34787, and dipyridamole. We have assessed their influence on the ability of platelets to convert arachidonate to malondialdehyde (MDA, a marker of thromboxane synthesis) and on the arachidonate-induced release reaction (release of 14C-serotonin from labelled platelets. Platelets from different individuals respond differently to some of these agents. Whereas similar concentrations of each of acetylsalicylic acid, indomethacin, flurbiprofen and tolmetin were required to inhibit MDA production in platelets from different donors, higher concentrations of these NSAIAs were sometimes required to inhibit the arachidonate-induced release reaction in platelets from some donors than were required in platelets from others. UK-34787 inhibited both MDA production and the release reaction in platelets from some donors, but in platelets from others it had little effect on release despite inhibiting MDA generation. Dipyridamole was more effective as an inhibitor of the platelet release reaction in platelets that were responsive to UK-34787 than in platelets that were not. These different effects of agents on platelets from different individuals might be relevant to their effectiveness in thromboembolic disease. Perhaps participants in clinical trials should be stratified according to the responsiveness of their platelets to the particular drugs under scrutiny.
Malondialdehyde
Thromboxane-A synthase
Thrombopoiesis
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Thrombin‐regulated platelet activation mediates a diverse range of vascular effects which may result in thrombus formation and stroke. Thromboxane (TxB 2 ) is thought to play a crucial role in the reinforcement of platelet activation following thrombin activation via TxB 2 formation in the platelet. We demonstrate that PAR1 and PAR4 work synergistically but through unique signaling pathways following activation in order to generate both TxB 2 as well as 12‐HETE. To investigate the signaling differences, we examined multiple biochemical and physiological steps involved in platelet activation including Rap1, aggregation, Ca 2+ mobilization and formation of 12‐HETE and TxB 2 . Inhibition of PIP 2 and PIP 3 significantly altered PAR1‐, but not PAR4‐mediated platelet aggregation and resulted in inhibition of TxB 2 , but not 12‐HETE. Additionally, the time course for PAR1‐mediated TxB 2 formation was faster compared to PAR4. Inhibiting PAR4 activation with YD3 only partially blocked thrombin‐mediated effects confirming the synergistic involvement of both PAR1 and PAR4 in this process. A better understanding of regulation of platelet function through PAR signaling pathways is crucial to developing a better class of anti‐platelet therapies with a lower profile for bleeding as a side effect. This study was supported in part by grants P50 HL081009 (to H.E.H.) and R00 HL089457 (to M.H.) from National Institutes of Health.
Thromboxane-A synthase
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In humans, activated platelets contribute to sepsis complications and to multiple organ failure. In our prospective analytical study of cases of the equine systemic inflammatory response syndrome (SIRS), we adapted a standard human protocol for the measurement of activated platelets and platelet-leukocyte aggregates (PLAs) in equine platelet-leukocyte-rich plasma (PLRP) by flow cytometry, and we investigated the hypothesis that activated platelets and PLAs are increased in clinical cases of SIRS. We included 17 adult horses and ponies fulfilling at least 2 SIRS criteria, and 10 healthy equids as controls. Activation of platelets was determined by increased expression of CD62P on platelets. Activated platelets and PLAs were measured before and after in vitro activation of platelets with collagen. Median expression of CD62P on platelets was significantly increased after activation in the control group: 1.45% (interquartile range [IQR]: 1.08-1.99%) initially versus 8.78% (IQR: 6.79-14.78%, p = 0.002) after activation. The equids with SIRS had significantly more activated platelets and PLAs in native PLRP than controls: CD62P 4.92% (median, IQR: 2.21-12.41%) versus 1.45% in controls (median, IQR: 1.08-1.99%, p = 0.0007), and PLAs 4.16% (median, IQR: 2.50-8.58%) versus 2.95% in controls (median, IQR: 1.57-3.22%, p = 0.048). To our knowledge, increased platelet activation and PLAs have not been demonstrated previously with flow cytometry in clinical cases of equine SIRS.
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Background The American Diabetes Association (ADA) 2003 diagnostic criteria divide impaired glucose tolerance (IGT) into isolated impaired glucose tolerance with normal fasting glucose (I-IGT, IGT+NFG) and impaired glucose tolerance combined with impaired fasting glucose (IGT+IFG), while the World Health Organization (WHO) 1999 criteria do not. The aim of this meta-analysis was to evaluate whether IGT should be divided into I-IGT (IGT+NFG) or IGT+IFG according to their risk of progression to type 2 diabetes. Methods The MEDLINE and EMBASE were searched to identify prospective cohort studies published in English prior to April 18, 2020. Review Manager 5.3 was used to calculate the pooled risk ratios (RRs) and 95% confidence intervals (CIs) as summary statistics for each included study. Results Sixteen eligible studies ( n = 147,006) were included in the analysis. The subsequent incidence of type 2 diabetes was lower in the I-IGT (IGT+NFG) group than in the IGT+IFG group (0.45 [95% CI 0.37, 0.55] according to WHO 1999 criteria and 0.59 [95% CI 0.54, 0.66] according to ADA 2003 criteria). It was higher in the I-IFG, I-IGT (IGT+NFG), and IGT+IFG groups than in the normoglycemic group (95% CI of 5.53 [3.78, 8.08], 5.21 [3.70, 7.34], and 11.87 [7.33, 19.20] according to the WHO 1999 criteria and 95% CI of 2.66 [2.00, 3.54], 3.34 [2.81, 3.97], and 6.10 [4.72, 7.88] according to the ADA 2003 criteria). In general, the incidence of diabetes in the IGT+IFG group was the highest in the prediabetic population. Conclusions The present meta-analysis suggested that the established WHO diagnostic criteria for IGT should be revised to separately identify individuals with IGT+NFG or IGT+IFG.
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Objective Human platelets vary in size, function, and age. Large platelets are often considered to be young platelets. Two situations have to be distinguished, normal steady state platelet production and increased platelet turnover. Here we focused on large and small platelets in humans during increased platelet turnover. To avoid artefacts by interfering factors (medication, comorbidities), we established a platelet apheresis model to deplete platelets from healthy volunteers with subsequent increased platelet production.
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Thromboxane B2
Thromboxane-A synthase
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P-selectin
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The function of 111 In‐labelled platelets has been assessed by collagen‐induced aggregation of platelets in samples of whole blood. The blood samples were drawn after injection of autologous 111 In‐labelled platelets in 19 subjects undergoing platelet kinetic studies. It was thus possible to measure the aggregability of labelled and unmanipulated platelets simultaneously. 111 In‐labelled platelets aggregated to the same extent as unmanipulated platelets when tested from 10 min to 24 h after injection of the labelled platelets. The results confirm the assumption that minimal damage is inflicted on the platelets during the isolation and labelling procedures, and support the concept that platelets manipulated in vitro may recover in vivo within a few minutes after reinjection.
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Background and Objectives: Hyperconcentration of platelets may lead to platelet activation and loss of platelet function. Materials and Methods: Platelet activation following hyperconcentration was assessed using flow-cytometric detection of platelet P-selectin expression and platelet swirling. Results: Platelet hyperconcentration led to a minimal increase in P-selectin expression and no differnce in platelet swirling. Conclusion: Hyperconcentration was not associated with a clinically significant change in platelet activation and had no significant effect on platelet quality as detected by pH and platelet yield.
P-selectin
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Abstract Background and Objectives: Hyperconcentration of platelets may lead to platelet activation and loss of platelet function. Materials and Methods: Platelet activation following hyperconcentration was assessed using flow‐cytometric detection of platelet P‐selectin expression and platelet swirling. Results: Platelet hyperconcentration led to a minimal increase in P‐selectin expression and no differnce in platelet swirling. Conclusion: Hyperconcentration was not associated with a clinically significant change in platelet activation and had no significant effect on platelet quality as detected by pH and platelet yield.
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